title: MST1 functions as a key modulator of neurodegeneration in a mouse model of ALS.
abstract: Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by loss of motor neurons. Dominant mutations in the gene for superoxide dismutase 1 (SOD1) give rise to familial ALS by an unknown mechanism. Here we show that genetic deficiency of mammalian sterile 20-like kinase 1 (MST1) delays disease onset and extends survival in mice expressing the ALS-associated G93A mutant of human SOD1. SOD1(G93A) induces dissociation of MST1 from a redox protein thioredoxin-1 and promotes MST1 activation in spinal cord neurons in a reactive oxygen species-dependent manner. Moreover, MST1 was found to mediate SOD1(G93A)-induced activation of p38 mitogen-activated protein kinase and caspases as well as impairment of autophagy in spinal cord motoneurons of SOD1(G93A) mice. Our findings implicate MST1 as a key determinant of neurodegeneration in ALS.
authors.affiliation: Laboratory of Cell Death and Human Diseases, School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
authors.forename: Jae Keun
authors.initials: JK
authors.lastname: Lee
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Shin
authors.forename: Sang Gil
authors.initials: SG
authors.lastname: Hwang
authors.forename: Byoung Joo
authors.initials: BJ
authors.lastname: Gwag
authors.forename: Ann C
authors.initials: AC
authors.lastname: McKee
authors.forename: Junghee
authors.initials: J
authors.lastname: Lee
authors.forename: Neil W
authors.initials: NW
authors.lastname: Kowall
authors.forename: Hoon
authors.initials: H
authors.lastname: Ryu
authors.forename: Dae-Sik
authors.initials: DS
authors.lastname: Lim
authors.forename: Eui-Ju
authors.initials: EJ
authors.lastname: Choi
mesh_terms: D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000503:physiopathology*; D000704:Analysis of Variance; D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology; D004789:Enzyme Activation / Q000235:genetics / Q000502:physiology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism / Q000502:physiology*; D020125:Mutation, Missense / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D013879:Thioredoxins / Q000378:metabolism; D000099317:Hippo Kinases
chemical_list: D017346:Protein Serine-Threonine Kinases; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D013879:Thioredoxins; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases
keywords: ROS; neurotoxicity